Process for preparing alkyl isodehydroacetates employing sulfur trioxide



Patented Aug. 19, 1952 PROCESS FOR PREPARING ALKYL ISODE-j HYDROACETATES EMPLQYING SULFUR TRIOXIDE James M. Straley and Brice S. Wininger, Kingsport, Tenn., assignors to Eastman Kodak Company, Rochester, Jersey N. Y., a corporation of New No Drawing. Application March 29, 1951,

Serial No. 218,268

'Ifhis invention relates 'to' the preparation of esterslof isodehydroacetic acid by'an improved 20 Claims. (ci.2e-'-s44) process employing sulfur trioxide as the condensing agent.

It is known that"alkyl'isodehydroacetates may be'prepared by condensing alkyl acetoacetates in o the presence of an acid condensing agent at room temperature or lo werft'emperatures and under ordinary atmospheric pressure. Thus, it is known that ethyl isodehydroacetate may be prepared by intro'ducmganhydrous hydrogen chloride into "cold ethyl acetoa'cetate' attemperatures near 0 CFan'd allowing the mixture to stand for a long period of time'on the order 'of' a couple of weeks at' room temperatures with usually an additional "cooling'tonear 0C., accompanied by the introduction of more hydrogen chloride. However; the

yields obtained by'sucha process rarely exceed 50 percent until at least two Weeks'have elapsed.

- It'is also "'knownthat similar results may be obtained when concentrated sulfuric acid is employed as thecondensing agent, the other condiincreased.

dehydroacetic acid was lowered. Furtherrit was foundnthat the proportion of this yield whichwas esterralso was diminished as the temperature was In U. s. Patent 2,529,917 dated November 14,

. 1950, a process is described for the preparation of esters of isodehydroacetic .acidemploying hydrogen chloride as the condensing agent at temperatures of from to 100 C and conducting the reaction in a closed vessel under autogenous. pressure. Judging by the yields obtained,.the use of hydrogen chloride seems superior to the other methods described in the prior art, ,but on a commercial scale, such a process imposes serious problems ,of. handling and corrosion. Furthermore,

anhydroushydrogen chloride is'quite expensive and, there is apparently little likelihoodof inexpensive recovery of it. Sulfuric acid and o leum are cheap but the yields obtained by their use as described in the. prior art are either low, or the desired esters formed are cqntaminated with considerable quantities of free isodehydroacetio acid tions being-substantially the-same as described '-for the-utilization of-hydrogen chloride. The extensive periods of timefor accomplishing the condensation reacti'om under suchconditions are necessarym order to obtain worthwhile yields. During the preparation of alkylisodehydroace- -tate's, the formation of-water during'thecondensation reaction togetherwith the presence of the acidic condensation agent, create a condition which is normally conducive of hydrolysis. Hydrolysis and other -side reactions are obviously :undesired land causetheproduction of contam- J inating byl-productsa Under the conditions described in the prior art; ethyl isodehydroacetate .has been preparedlb-y condensing a solution consisting of six;equivalents (3. mols)v of concentrated "sulfuric acidper. mol of ethyl acetoacetate at room .temperatureiabout 25C.). for 10 to 14 days with -aconsequent 82 percent yield of an approximately .half-and-half mixturerof ethyl isodehydroacetate and. isodehydroacetic acid-z Since the free acid is not a .desired product of our process, such ayield 'of only;41 percent of the .esteris. not very satisfactory. The free, iacidfiobtained is difiicult to westeriiy. and its formation is therefore not dev.sire gl Upon further investigation of the use of s1ilf uri0- ,ac i d as thecondensing agent, it wasiourid engine. side reactions involved at ine s e u es nd re i i q n erii e i rsultedin' so many undesirable .by-product's that satisfactory yields ,or. alkyl' isodehydroacetates were not obtainable even though increased rates l of reaction. did accompany the'increase inithe temperatures. It was also found that whenthe temperaturesioi the condensation were raised, the

' over-all yield of iethyl isodehydroacetate'and isowhich cannotbe, economically converted o the esters desired. 4 o I I We haveno-w, discovered a process which is not encumbered by any of these disadvantages. We haveiound that sulfurtrioxide can be used to promote the self-condensation of esters of acetoacetic acid to form the correponding. esters of isodehydroacetic acid. Anhydrous sulfur trioxide is now available commercially at a reasonable price and its use is not accompanied by inordinate corrosionor handling problems. Furthermore, "by using anhydrous sulfur trioxide, free'i'sodehy'di'oacetic acid is formed in quantities which are relatively insignificant from a manuiacturin'gviewpoint; that is,it is not formed in 'arni'iunts'. s'ufficient'Ito result infthe' solid complex whichishn undesirable by product when sulfuric acid is employed. The principal reaction which takes place in accordance with our invention can be representedas v wl'iereiri Brepifesents an aky ram-a.)

i above.

We have" further found that the use of an anhydrous solvent which does not interfere with the course of the condensation reaction is advantageous in the conduct of this reaction. More! L over, it has been discovered that when lower aliphatic alcohols are employed-as such solvents that their use permits the employment of higher" temperatures without lowering the yield. While alcohol is formed in the reaction, as indicated in the above chemical equation, the addition of an alcohol to the reaction mixture actually increases the yields of the desired product. This is unexpected inasmuch as the law of mass-action would indicate that the presence of an alcohol would tend to cause the reaction to reverse itself.

It is an object of our invention to provide an improved process for the manufacture of alkyl esters of isodehydroacetic acid. A further object or our invention is to provide a superior condensing agent for employment in the condensation of alkyl esters of acetoacetic acid to form the alkyl esters of isodehydroacetic acid. Another object of" our invention is to provide effective solvents which serve as advantageous reaction mediums for the conduct of the condensation reaction. hereinafter.

In practicing our invention, we have found that while temperatures at least as high as 80 C. may be used, it is more advantageous to use temperatures no higher than room temperatures. It is preferred to employ temperatures, especially during the mixing of the components of the reaction mixture, which are in the vicinity of C. or lower. The lowest temperature employable C. inasmuch as the latter temperature has been employed satisfactorily.

Although it is not necessary for the reaction to be conducted in a solvent, the use of certain solvents is advantageous as has been explained Such solvents can include the aromatic hydrocarbons such as benzene, toluene, xylene, etc., or halogenated aliphatic hydrocarbons.

However, the preferred solvents are aliphatic al- Other objects will become apparent I has not been determined but it is clearly below.

cohols such as ethanol, isopropanol, butanol,

hexanol, etc. Generally, such alcohols which can be advantageously employed are those alcohols which has been dissolved in a solvent which does not interfere with the course of the condensation thereof, it such a solvent is being employed.

The alkyl acetoacetates which can be advantageously employed include methyLethyl, and

n-propyl acetoacetates' However, any of the lower alkyl esters can be employed. Thus we can employ any of the alkylacetoacetates,especially those containing from one to six carbon atoms in the alkyl radical, thereby producing alkyl isodehydroacetates which correspond thereto In conducting the reaction it is advantageous to employ approximately 1 mol of the solvent for each 2 mols of the alkyl acetoacetate being condensed. However, larger or smaller quantities of the solvent can be employed. As has been pointedout above, the condensation reaction can ganic layer from the reaction mixture.

= be employed without any solvent. .Theiiquantity of sulfur trioxide which can beadvantageously employed may be varied considerably. However, one mol of sulfur trioxide per mol of alkyl acetoacetateis an advantageous proportion. Higher and lower proportions can also be employed. It is advantageous to dissolve the sulfur trioxide in a solvent such as a liquid hydrocarbon, which can be either aliphatic or aromatic, and halogenated derivatives thereof. Examples of such solvents include'benzene, toluene, xylene, carbon tetrachloride, etc. Such solvents also serve to separate the alkyl isodehydroacetate as an or- When suchsolvents are employed, it is advantageous to dissolve the sulfur trioxide therein prior to its .introduction into the alkyl acetoacetate which is to becondensed; however; the sulfur trioxide canbe introduced directlywitliout previous dissolution thereof. The hydrocarbon solvents can be introduced into the reaction mixture either at once or after thecondensation isco'mpleted or not at all. 7

During. the introductio'n'of the sulfur trioxide into the alkyl acetoacetate' (or vice versa), it is advantageous to maintain the temperature of the mixture below 20 CL. Evenmore advantageously, the temperature can be maintained at around 0 C. However, highertemperaturescanalso be employed. After the. admixture of the components of thereaction mixture has been completed, the temperaturemaybe permitted to rise to room temperature or it mayberaised to. an elevated temperature ,ofabout 40' C. Higher temperatures than 40 C. can also'be employed.

However, it is usually advantageous to maintain the temperature duringthe reaction period at 25 C. or lower. v

. Theadmixing operation should ebeconducte'd slowly over a period of-time whichspermitsthe maintenance of the temperature within the desired range. This periodof time obviously .de-

,pends upon the cooling means available. length of: time from a few minutes to-sevetal time. x .A'dvantageously', from;- 14 to; 60* rhours..ca;n .be, employed, depending upon the .otherconditions under which the reaction conducted.

Ordinarily, periods of timev employed sneedz-n'ot exceed .24., hours.

When the L. reaction is conducted: at or above'r'oom temperatures;the-period of time should be reduced to" avoid unduetforma- .tionof. undesirable. products thus 12 hours under somesuch circumstances is: frequent1y.:.suflic ient. Upon substantial completion on the condensation, the alkyl isodehydroacetatecan be separated by pouring the reaction mixture onto'ioe orinto coldwater and- I adding a nonvv'a'te'r- 'mi scib1ej-SOIvnfi s uchas" the hydrocarbons referred to above" if-they'arenot already present. The'orga'ni'c' layer which" forms contains thedes'ire'd product which eamthen be separated out by'distillatidn and can be further purifiedfr-bfy any suitable-means} Other methods crs'eparating the: 'productfrom the reaction: mixture are alsb' clearly possible and can be 'applie'd.

rue following ex mmeswm servei. tofurtlier "illustrate; the manne'rf of ziriactic ngiour' ,invfir 11011; an arts are parts by Weighti A solution of 50 parts renewal Example-1m of ethanol in 2' parts (2--'mols) of ethyl acetoacetatdW'asprepared. Keeping the admixing temperature below 0.,

' 160 parts (2 mols) of-S03 was fed in-withgood agitation f during a: period of Z hours': The'reaction"mixture wasthen-allowed to stand-1 12 hours at-roorn temperature; It was then'poured onto ice and 400 parts of benzene wasf added.

The organic layer which formed was separated off and distilled' There was thus'obtained 8'7 parts of ethyl isodehydroacetate which represents'a 56%"yieldbasedon the amount of ethyl acetoacetate which reacted; there being 51 parts of the latter compound which remained un-' [changed in the reactionproductif Theethyl 'isowas kept below ,20"v Gland the'reaction mixture was allowed to stand 'at --5 C. to- 0 C.

There was thus obtained91 parts or ethyl isodehydroacetate which represented a 60% yield; 61. parts of ethyl acetoacetateiremained unchanged. v s

" Example 3.

The procedure of Example 51 was repeated exactly except'that 80 parts of .n-butanol was employed in place of the ethanol, the admixing temperature was keptat --5C. to 0 0., and the-reaction mixture was allowed to stand 60 hours at 0 C. There was thus obtained 95 parts of ethyl isodehydroacetate which represented a 64% yield; '65 parts" of ethyl acetoacetate remained unchanged. 5

Isopropanol has also been employed in accordance with the procedure set forth in the above example whereby it replaces the n-butanol.

Example 4 The procedure of Example 1 was repeated exactly except that 350 parts of benzene was incorporated into the ethanol solution prior to the introduction of $03, the admixing temperature was kept below 0., the reaction mixture was allowed to stand 4 hours at 40 C., and no benzene was added after pouring onto ice. There was thus obtained 92 parts of ethyl isodehydroacetic acid which represented a 60% yield; 57 parts of ethyl acetoacetate remained unchanged.

Example 6 shows that adding the S0: to the ethyl acetoacetate solution as in Example 1 is 5 more advantageous than the modified reverse procedure of Example 6 wherein the ethyl acetoacetate was added to a solution of S03.

Example 7 The procedure of Example 1 was repeated exactly except that the S03 was first dissolved in 260 parts of carbon tetrachloride prior to the addition thereof to the ethyl acetoacetate solution, the admixing temperature was kept below 20 0., the reaction mixture was allowed to stand 20 hours at 5 C., and no benzene was added after pouring onto ice. There was thus obtained 112 parts of ethyl isodehydroacetate which rep-- resented a 70% yield; 45 parts of ethyl acetoacetate remained unchanged.

- 7 Example shows that the V SC); in the iorm of a solution; can be advantageously added; to the ethyl acetoacetate. 1

m b The procedure of Example 1 ,yvasfrepeated exactly except that no ethanolyvasemployed,

and-the reaction mixture was allowed stand 40 hours at 5-.,C.. There was thus obtainedfil parts of ethyl isodehydroacetate which. repre- .sented a 34% yield; 28 parts of ethyl acetoacetate remained unchanged. Example 8 shows that it is more advantageous .-.-to employ a solventifor the ethyl =acetoacetate ,beingzcondensed as in Example 1 thantoromit such asolvent. as inExample 8.

. Example} 1 The procedure of Example 11 was repeated exactly except that an'approximately equivalent molecular quantity (230'parts). of methyl "acetoacetate was employed" without dissolutionin ethanol (no solvent for the'methyl acetoacetate 'of methyl isodehydroacetate Y which represented a yield of40%; 35 partsof-methylacetoacetate remained unchanged. The methyl isodehydroacetate boiled at 110 C; at 2mm. of Hg pressure'and had a melting point at 65-66 C. It can be further purified by redistillation-,'fra ctionation, or any other suitable means if desired.

Example 9 shows that the omission of a solvent for the acetoacetic esterbeing condensed results in a-less adv antageousyield than whensuch a solvent is employed as in Example '7 or 10; i

Example 10 The procedure of Example 9 was repeated exactly except that the methylacetoacetate was dissolved in 50 parts ofethanol prior to the addition of the S03 dissolved in carbon tetrachloride. There was thus obtained 84 parts of methyl isodehydroacetate (which boiled at -160 C. at 10 mm. of Hg pressure) and which represented a yield of 56%; 40 parts of methyl acetoacetate remained unchanged.

Example 10 represents an equivalent procedure to that of Example 7 except for the use of the methyl instead of the ethyl ester. As in Example 7, Example 10 shows that the SO: in the form of a solution can be advantageously added to methyl acetoacetate.

The methods disclosed in the above examples are clearly subject to many modifications such as in the proportion of sulfur trioxide to alkyl acetoacetate, the proportion of solvent employed, the temperatures, reaction times, etc.

What we claim as our invention is:

1. A process for preparing an alkyl isodehydroacetate comprising condensing an alkyl aceto-' 4. A process for preparing ethyl isodehydrm a eotpsi 7. =A process asdefined in claim GWherein-"the sulfur'trioxide is added to the ethyl acetoacetate isoluti'on. I ":8. :Avprocessas definediin claim '7? wherein the :sulfurtrioxide isziiissolved in a solvent-selected from the group consistinglloraromatic andicaliphatic liquid hydrocarbons and chlorinated hydrocarbons prior "to its addition to the ethyl fincetoacetate-solution.

ikxprocessastdefinedzin claim ;8w herein:the

Fsuliur itrioxi'de :solvent :is Icarbon tetrachloride.

10. niprocesszas-defined iniclaim 9 whereinthe temperature is tmaintained below about 20 1C. iwhile adding the, sulfur trioxide solution.

.11. A 313200888 for :preparing @an @a'llcyl 'isodehy- -.droacetate comprising --adding sulfur trioxide at :a temperature of from about-520 :toabout 20C. 4701a; solution .ofwan-alkjyl lacetoacetate -cont'aimng .:from 1 :to :6 carbon atoms-in the alkyl group dissolvedinia solvent=whichwdoes not interiere with the courseof'thecondensation reaction,-.and-then q-lallowing 'ithet reaction toe-continue ;f or. from -about 3120 about .60 :hours at a ten'iperature ;of -from about -10? to about;40 C. v

12. Amr'ocessior ;.-preparing an' alkyl :isodehy- .droacet-ate comprising adding sulfur trioxide :to a rsolutionwin an alcohol having the formula -G11H2n;+1OH.wherein n is an integer from 1 tot of Ian :al-kyhacetoacetate containing from -1 to 6 carbomatomsin the alkyl group at a temperatureof from about ---20 toiab'out .20 .C. and then allow-- ing the reaction to continue for from about 4 to the :alkyl-v-group is .ethjl.

vacetoacetate solution.

".acetoacetate solution.

about 60 hours at' a temperature of from about -.l0 to about 20.

, the-V sulfur Itrioxide is dissolved? in a .solventsel ectedfrom the group consisting ofarornatic and aliphatic -liquid hydrocarbons and 'ichiloi'inate'd hydrocarbons ,prior to its addition .to the ethyl 15. A ;-.process {as defined in claim' 114 wherein the-alcohd lisethanol V I p 12 6. 15.-process as, definediljinclaim 5 15 wherein the sulfur trioxi'de solvent is carbon tetrachloride. v

17. A process .aisjdefinedf in claim 16 wherein the initial mol ratio of .sfii'mr ltrio xide Ito Lethyl .acetoacetatelisiabout unity. I

1'8. A process for ,preparingjinethyl isodehydroace'tate comprising adding sulfur 'tr-ioiiide"to a solution in an alcohol haVing the' formula CnHZn-l-lOH wherein nsis-ani'integer from 1 to 6 of methyl acetoacetate at a temperature of .from about '20' to about*20 C. andithenallowing about 40 C. p

19. A process as defined in claim "18 wherein :the sulfur v trioxide "is dissolved in a solvent sele'cted'from the group "consistingof aromatic and aliphatic liquid hydrocarbons and chlorinated hydrocarbons prior to-its "addition to the ethyl 20. Agprocess :as idefine'd in claim 19 wherein the alcoholf is ethanol, :the sulfur trioxide solvent is carbon tetrachloride and the rmol ratiog of rsu1- zfuratrioxide to methyl-acetoacetate,isaboutwunity.

. 'EIAME 'STRALEY.

' I-TBRICE' No references'ci'ted. 

4. A PROCESS FOR PREPARING ETHYL ISODEHYDROACETATE COMPRISING CONDENSING ETHYL ACETOACETATE AT A TEMPERATURE OF FROM ABOUT -20* TO ABOUT 40* C. IN THE PRESENCE OF SULFUR TRIOXIDE AND AN ALCOHOL HAVING THE FORMULA CNH2N+1OH WHERE N REPRESENTS AN INTEGER FROM 1 TO
 6. 